U.S. Pat. No. 5,382,600 discloses that (substituted) 3,3-diphenylpropylamine is effective for the treatment of overactive bladder. In particular, the above patent teaches that 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, which has a general name of tolterodine [formula 1] and has been known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine, is useful for the treatment of overactive bladder. Tolterodine is a compound disclosed in Example 22 of U.S. Pat. No. 5,382,600. Tolterodine is preferably manufactured by a method disclosed in WO Publication No. 98/29402.
H. Postlind et al. reported that tolterodine is a Muscarinic receptor antagonist [Drug Metabolism and Disposition, 26(4): 289-293 (1998)]. It has been on the commercial market as Detrol (Pharmacia). Tolterodine is orally administered in the form of a tablet for the treatment of overactive bladder. Active metabolites of tolterodine are hydroxytolterodines.
U.S. Pat. No. 5,559,269 and H. Postlind et al. disclosed hydroxytolterodine [Drug Metabolism and Disposition, 26(4): 289-293 (1998)].
U.S. Pat. No. 5,559,269 teaches that the above compound is effective in the treatment of overactive bladder, and it has been reported that hydroxytolterodine has an anti-muscarine property [Pharmacol. Toxicol., 81: 169-172 (1997)].
WO Publication No. 98/29402 discloses tolterodine salts of methane sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, citric acid, tartaric acid, fumaric acid, maleic acid, CH3—(CH2)n-COOH (here, n is an integer of 0-4), HOOC—(CH2)n-COOH (here, n is an integer of 0-4).
WO Publication No. 02/34245 discloses the uses of tolterodine as a treatment for asthma, COPD and allergic nasal inflammation.
Tolterodine, a commercial therapeutic agent for the treatment of overactive bladder, is administered in the form of a film-coated tablet comprising 1 mg, 2 mg or 4 mg of tolterodine L-tartrate to be released in the gastrointestinal tract. With regard to drugs, customers have always asked a selective delivery form to improve the quality of their lives such as excellent efficacies and/or convenient treatment.
‘Overactive bladder’ a newly coined medical term, refers to a physical condition with symptoms of urinary frequency, urinary urgency or urgent urinary incontinence.
‘Urinary frequency’ refers to a condition of a person having urination more than 8 times daily, and it may accompany a desire for urination even after urination.
‘Urinary urgency’ refers to a condition of a person when urination cannot be endured any more and thus urgent urination is required.
‘Urgent urinary incontinence’ refers to a condition of a person when urine is being leaked out due to sudden intolerable urination desire.
About more than 50 million people around the world suffer from ‘Overactive bladder’ About 22% of adults aged 40 or older have the overactive bladder symptom. It develops in practically both males and females in all age groups but more frequently in females. It is caused by extremely frequent contraction of detrusor muscle, the smooth muscle of overactive bladder. That is, the bladder muscle contracts more frequently than normal or contracts when not necessary thereby giving out a sudden signal for urination. The major cause in most cases has not been yet identified but in some patients it appears to be due to the defect in neurotransmission or neuronal damage resulted from surgery or baby delivery. In case of men, it is very common to have both prostatic hypertrophy and overactive bladder.
Overactive bladder is a disease that often accompanies lack of sleep, decrease in work efficiency, avoidance of sexual life, depression and social phobia resulted from lack of information and a sense of shame on the disease, thus greatly lowering the quality of life. The correlation between the diseases including overactive bladder and quality of life was investigated and the result (SF-36 Questionnaire) showed that overactive bladder decreases the quality of life further as compared to other adult diseases such as diabetes and hypertension. Therefore, there is an urgent need for the development of a novel pharmaceutical compound to restore the quality of life of the overactive bladder patients.
From the pharmacological point of view, tolterodine (formula 1) is preferred to be in a free base form. However, it is very hard to handle during the manufacturing process because it is in a liquid form with high viscosity thus lowering the yield, and has poor storage stability and thus it is generally administered in the form of an acid salt with a pharmaceutically acceptable acid.
The acid salt of tolterodine currently used for the treatment of overactive bladder is tolterodine tartrate (formula 2)

Korean Pat. No. 90,479 discloses that a pharmaceutically acceptable salt should meet the following four physicochemical requirements: (1) excellent solubility (2) excellent storage stability (3) non-hygroscopicity (4) processability into tablets. However, it is not easy for a pharmaceutically acceptable salt to meet all the above listed conditions. In fact, even tolterodine tartrate decomposes itself within a few weeks when placed in a solution thus posing a stability problem. Further, its transdermal absorption rate is much lower than that of tolterodine free base form.